Neuronal plasticity accompanying development and experience-dependent processes facilitates the establishment and refinement of the nervous system, while presenting significant challenges to the functional stability of the neural networks. The nervous system uses a variety of compensatory mechanisms to cope with perturbations. Recent studies suggested that structural plasticity serves as a major component for neuronal homeostasis. Our previous studies have demonstrated experience-dependent plasticity in the developing Drosophila larval visual circuit, in which ventral lateral neurons (LNvs), the postsynaptic targets of larval photoreceptors, exhibit robust structural plasticity of their dendritic arbors when animals are subjected to different visual experience. These observations established a genetically tractable model system for mechanistic studies on the activity-dependent regulation of developmental plasticity. To investigate the contribution of genetic factors in the activity-dependent regulation of dendrite morphology, we performed forward genetic screens and cell type specific manipulations. A number of candidate genes, including cell adhesion molecules, cytoskeleton associated proteins and other critical components for synaptic organization were identified using these approaches. In addition, using two-photon time-lapse live imaging of LNvs in the developing larval brain, we established temporal profiles for dendrite morphogenesis, synapse formation and fast dendrite dynamics, and observed the strong influence on these processes imposed by visual experience. Our experiments showed that experience-dependent homeostatic mechanisms primarily target dynamic dendritic filopodia in tuning the maturity of dendritic arbors, which defines the capability for synaptogenesis and subsequent growth. These findings provided novel insights into the cellular and molecular mechanisms underlying homeostatic structural plasticity in the developing neural circuit. To study global transcriptional changes associated with chronic elevation of synaptic activity, we performed cell type-specific transcriptome profiling of LNvs and identified activity-modified transcripts that are enriched in neuron morphogenesis, circadian regulation, and lipid metabolism and trafficking. Using bioinformatics and genetic analyses, we validated activity-induced isoform-specific up-regulation of Drosophila lipophorin receptors LpR1 and LpR2, the homologues of mammalian low-density-lipoprotein receptor (LDLR) family proteins. Furthermore, our morphological and physiological studies uncovered critical functions of neuronal LpRs in maintaining the structural and functional integrities in neurons challenged by chronic elevations of activity. Together, our findings identify LpRs as novel molecular targets for activity-dependent transcriptional regulation and reveal the functional significance of cell-type specific regulation of neuronal lipid uptake in experience-dependent plasticity and adaptive responses.
